Compositions including modafinil for treatment of eating disorders and for appetite stimulation

ABSTRACT

Modafinil is effective in improving symptoms of eating disorders or in stimulating appetite.

BACKGROUND OF THE INVENTION

[0001] 1. Field of the Invention

[0002] The present invention is related to the fields ofneuropharmacological agents, including agents that are useful in thetreatment of eating disorders and agents that stimulate appetite toproduce weight gain in both human and animals in need thereof.

[0003] 2. Description of Related Art

[0004] Modafinil (C₁₅H₁₅NO₂S), 2-(benzhydrylsulfinyl) acetamide, or2-[(diphenylmethyl) sulfinyl] acetamide, is a synthetic acetamidederivative with wake-promoting activity, the structure of which has beendescribed in French Pat. No. 78 05 510 and in U.S. Pat. No. 4,177,290.Modafinil was tested in combination with various agents includingapomorphine, amphetamine, reserpine, oxotremorine, hypnotics, yohimbine,5-hydroxytryptophan, monoamine oxidase inhibitor (I.M.A.O.), and inseveral behavioral conditions, as described in the cited patents. Theconclusion from such tests is that modafinil presents aneuropsychopharmacological spectrum characterized by the presence ofexcitation with hyperactivity and hypermotility; and by the absence ofstereotypy except in strong doses, and as potentiating the effects ofapomorphine and amphetamine. A method of preparation of a racemicmixture is described in the '290 patent and a method of preparation of alevorotatory isomer is described in U.S. Pat. No. 4,927,855 (bothincorporated herein by reference). The levorotatory isomer is reportedto be useful for treatment of hypersomnia, depression, Alzheimer'sdisease and to have activity towards the symptoms of dementia and lossof memory, especially in the elderly.

[0005] Modafinil has also been described as an agent with activity inthe central nervous system, and as a useful agent in the treatment ofParkinson's disease (U.S. Pat. No. 5,180,745); in the protection ofcerebral tissue from ischemia (U.S. Pat. No. 5,391,576); in thetreatment of urinary and fecal incontinence (U.S. Pat. No. 5,401,776);and in the treatment of sleep apneas of central origin (U.S. Pat. No.5,612,378). U.S. Pat. No. 5,618,845 describes modafinil preparations ofa defined particle size less than about 200 microns that is more potentand safer than preparations containing a substantial proportion oflarger particles. Preparations of modafinil have not been described,however, for use in treating eating disorders, or as appetitestimulants.

[0006] The hypothalamus plays a central role in the integrated controlof feeding and energy homeostasis. Two neuropeptides (orexin-A andorexin-B, also known as hypocretin −1 and −2) have been identified thatare derived from a common precursor, preprohypocretin. These peptidesare reported to be localized in neurons within and around the lateraland posterior hypothalamus in adult rat brain, and have been shown tobind to and activate G protein-coupled receptors (Sakurai et al., Cell92:573-585, 1998), and are also reported to stimulate appetite and foodconsumption (Wolf, Nutr. Rev. 56:172-173, 1998). Although the appetitestimulating neuropeptides may prove useful for stimulating appetite,and/or promoting weight gain in a variety of situations, such as eatingdisorders including anorexia nervosa, disease related weight loss, oreven in agricultural applications such as promoting faster weight gainin weanling animals, it is difficult to administer peptides that areactive in the brain and central nervous system by an oral route. Thereis still a need, therefore for an oral preparation for treatment ofeating disorders or for promotion of weight gain.

SUMMARY OF THE INVENTION

[0007] The present disclosure provides a novel use for modafinil intreatment of eating disorders and in stimulating appetite in humanssuffering from an eating disorder, or who want or need to gain weightfor athletic performance or for cosmetic reasons. The present disclosurealso provides novel veterinary or agricultural uses for modafinil instimulating appetite and increasing the rate of weight gain in animals,particularly young animals or weanlings, and more particularly younganimals of species that are utilized for meat. Although the orexinpeptides are described as appetite stimulants, modafinil offers certainadvantages over those peptides in the compositions and methods disclosedbecause modafinil has been shown to be an effective oral treatment withactivity in the brain and central nervous system. As such, modafinil ismore convenient to administer than a peptide agent would be, which mustoften be injected in order to be effective.

[0008] As such, the present invention may be described in certainembodiments as a method of treating an eating disorder in a mammalcomprising administering to said mammal an amount of a modafinilcompound effective to stimulate the appetite of said mammal. The presentinvention may also be described in certain embodiments as a method ofpromoting weight gain in a mammal comprising administering to saidmammal an amount of a modafinil compound effective to stimulate theappetite of said mammal.

[0009] An aspect of the present disclosure is also a method ofincreasing appetite in a mammal comprising administering to said mammalan amount of a modafinil compound effective to increase the appetite ofsaid mammal. A further aspect of the present disclosure may also bedescribed as a method of treating a mammal suffering from the symptomsof an eating disorder comprising administering to said mammal apharmaceutical composition comprising a modafinil compound in an amounteffective to stimulate orexin activity in the central nervous system ofsaid mammal.

[0010] In certain preferred embodiments of the invention, a mammal orsubject to receive a modafinil compound may be a human or an animal, andin particular animals such as a bovine, ovine, caprine, or porcineanimal. Such animals are also described as cows, calves, pigs, sheep, orgoats, and may include various exotic animals that are raised foragricultural uses, for showing or for hunting, for example. It isunderstood that the present methods would also be useful for enhancingappetite in pets, such as dogs and cats, for example.

[0011] In certain preferred embodiments, a modafinil compound as used inthe practice of the disclosed compositions and methods is modafinil. Asdisclosed herein and as used in the compositions and methods of thepresent invention, a modafinil compound may include a racemic mixture,and may be in an acid form, such as a metabolic acid of modafinil or abenzhydrylsulfinylacetic acid, a sulfone form, a hydroxylated form, aconjugated form such as a modafinil compound conjugated to a protein, apolysaccharide, a glucuronide or a sulfate, or a polymorphic form, itmay include compounds containing isosteric replacements of the phenylgroups of modafinl, and polymorphic species or analogs of modafinil, orderivatives of cogeners and prodrugs, particularly those preparationsthat stimulate activity in the TMN, or that activate orexin neurons inthe central nervous system when administered to a mammal. Prodrugs areknown in the art as compounds that are converted to the active agent(modafinil) in the body of a subject.

[0012] The compositions and methods disclosed herein are useful, incertain embodiments, in the treatment, stabilization, or prevention ofeating disorders in mammals, or humans, for example, and in particularin the treatment of anorexia nervosa, binge eating disorder, bulimianervosa, undernutrition or malnutrition due to infancy, pregnancy orlactation, old age, or chronic disease, or in wasting associated withvarious diseases such as AIDS or AIDS Related Complex, for example.

[0013] Effective dosages as described herein include, but are notlimited to an amount from about 1 to about 400 mg, or from about 100 toabout 400 mg, or about 200 mg per daily dose for an adult human, or anequivalent dose for a human child or an animal. It is well known in thepharmaceutical art to prescribe drugs based on the body weight of asubject and calculating doses for humans or animals based on the presentdisclosure is well within the skill of a practitioner in the art. In analternate method of describing an effective dose, an effective amountmay be described, in certain embodiments as an amount that is effectiveto achieve a serum level of modafinil of from about 0.05 to about 20:g/ml, or from about 1 to about 20 :g/ml in an animal or a human.

[0014] Preferred formulations include compositions in which a modafinilcompound is formulated for oral administration, or more preferably thoseinn which a modafinil compound is formulated as a tablet. Preferredtablets contain lactose, corn starch, magnesium silicate, croscarmellosesodium, povidone, magnesium stearate, or talc in any combination. It isalso an aspect of the present disclosure that a modafinil compound maybe incorporated into a food product or a liquid.

[0015] In certain aspects, the present disclosure includespharmaceutical compositions in unit dose form, for use in treating aneating disorder in a subject susceptible to the development of orsuffering from an eating disorder, which comprises:

[0016] an amount of a modafinil compound such that one or more unitdoses thereof are effective to stabilize or improve the symptoms of aneating disorder in said subject upon periodic administration.

[0017] Also in certain aspects, the present disclosure includesveterinary compositions in unit dose form, for use in increasingappetite in an animal, which comprises:

[0018] an amount of a modafinil compound such that one or more unitdoses thereof are effective to increase the appetite of an animal uponperiodic administration.

[0019] An aspect of the present disclosure may also be described as atherapeutic package for dispensing to, or for use in dispensing to, amammal being treated for an eating disorder, comprising:

[0020] (1) one or more unit doses, each such unit dose containing anamount of a modafinil compound such that said one or more unit dosesthereof are effective to stabilize or improve a symptom of an eatingdisorder in said mammal upon periodic administration and the unit dosesbeing administered periodically, and

[0021] (2) a finished pharmaceutical container therefor,

[0022] said container containing (a) said unit dose or unit doses and(b) labeling directing the use of said package in the treatment of saidmammal.

[0023] Although the compositions and methods disclosed herein have beendescribed in light of certain preferred embodiments, it is understoodthat the modafinil compounds described herein may be orally administeredwith an inert diluent or an assimilable edible carrier, for example. Thecompositions may also be enclosed in hard or soft shell gelatin capsule,compressed into tablets, or incorporated directly with the food of thediet. For oral therapeutic administration, the active compounds such asmodafinil may be incorporated with excipients and used in the form ofingestible tablets, buccal tablets, troches, capsules, elixirs,suspensions, syrups, wafers, and the like, although tablets are thegenerally preferred method of administering modafinil. Such compositionsand preparations should contain at least 0.1% of active compound. Thepercentage of the compositions and preparations may, of course, bevaried and may conveniently be between about 2 to about 60% of theweight of the unit.

[0024] The tablets, troches, pills, capsules and the like may alsocontain any of the following: a binder, as gum tragacanth, acacia,cornstarch, or gelatin; excipients, such as dicalcium phosphate; adisintegrating agent, such as corn starch, potato starch, alginic acidand the like; a lubricant, such as magnesium stearate; and a sweeteningagent, such as sucrose, lactose or saccharin may be added or a flavoringagent, such as peppermint, oil of wintergreen, or cherry flavoring, forexample. When the dosage unit form is a capsule, it may contain, inaddition to materials of the above type, a liquid carrier. Various othermaterials may be present as coatings or to otherwise modify the physicalform of the dosage unit. For instance, tablets, pills, or capsules maybe coated with shellac, sugar or both. A syrup of elixir may contain theactive compounds sucrose as a sweetening agent methyl and propylparabensas preservatives, a dye and flavoring, such as cherry or orange flavor.Of course, any material used in preparing any dosage unit form should bepharmaceutically pure and substantially non-toxic in the amountsemployed. In addition, the active compounds may be incorporated intosustained-release preparation and formulations.

[0025] In certain embodiments, the disclosed compositions may beformulated to be administered by use of a skin patch, or transdermaldelivery system. The administration of the modafinil compositionsdescribed herein transdermally may be accomplished by any of a number ofsystems known in the art. Examples of systems that may be adapted foruse with the compositions described herein include those systems oftransdermal administration described in U.S. Pat. No. 4,816,252; U.S.Pat. No. 5,122,382; U.S. Pat. No. 5,198,223; U.S. Pat. No. 5,023,084;U.S. Pat. No. 4,906,169; U.S. Pat. No. 5,145,682; U.S. Pat. No.4,624,665; U.S. Pat. No. 4,687,481; U.S. Pat. No. 4,834,978; and U.S.Pat. No. 4,810,499 (all incorporated herein by reference.

[0026] These methods typically include an adhesive matrix or drugreservoir system and may include a skin permeation enhancement agentsuch as ethanol, polyethylene glycol 200 dilaurate, isopropyl myristate,glycerol trioleate, linolenic acid saturated ethanol, glycerolmonooleate, glycerol monolaurate, n-decyl alcohol, capric acid, andcertain saturated and unsaturated fatty acids, and their esters,alcohols, monoglycerides, acetate, diethanolamides andN,N-dimethylamides (See for examples, U.S. Pat. No. 4,906,169).

BRIEF DESCRIPTION OF THE DRAWING

[0027] The following drawing forms part of the present specification andis included to further demonstrate certain aspects of the presentinvention. The invention may be better understood by reference to thisdrawing in combination with the detailed description of specificembodiments presented herein.

[0028]FIG. 1 depicts data orexin immunoreactive neurons (open bars) andorexin/fos irmmunoreactive neurons (shaded bars) in the perifomicalregions of mice brains in mice treated with modafinil or vehicle.

DETAILED DESCRIPTION

[0029] Modafinil is an agent with activity in the central nervoussystem, and has been developed as a treatment for excessive daytimesleepiness associated with narcolepsy. The primary pharmacologicalactivity of modafinil, like amphetamine-like agents, is to promotewakefulness. Modafinil promotes wakefulness in rats (Touret, et al.,Neuroscience Letters, 189:43-46 (1995); Edgar and Seidel, J. Pharmacol.Exp. Ther., 283:757-69 (1997)), cats (Lin et al., Brain Research,591:319-326 (1992)), canines (Shelton et al., Sleep 18(10):817-826,(1995)) and non-human primates (DS-93-023, pp 180-181; Hemant et al.,Psychophannacology, 103:28-32 (1991)), as well as in models mimickingclinical situations, such as sleep apnea (English bulldog sleepdisordered breathing model) (Panckeri et al, 1996) and narcolepsy(narcoleptic canine) (Shelton et al., Sleep 18(10):817-826, (1995)).Modafinil has also been demonstrated to be a useful agent in thetreatment of Parkinson's disease (U.S. Pat. No. 5,180,745); in theprotection of cerebral tissue from ischemia (U.S. Pat. No. 5,391,576);in the treatment of urinary and fecal incontinence (U.S. Pat. No.5,401,776); and in the treatment of sleep apneas of central origin (U.S.Pat. No. 5,612,378). U.S. Pat. No. 5,618,845 describes modafinilpreparations of a defined particle size less than about 200 microns thatis more potent and safer than preparations containing a substantialproportion of larger particles.

[0030] Various neuroanatomical pathways have been investigated for theirrole in inducing and maintaining wakefulness, and some of the work haspointed to the potential role of the tuberomamillary nucleus (TMN)(Sherrin et al., Science 271:216-219, 1996). A study by Lin et al.,(Proceedings of the National Academy of Science, USA 93:14128-14133,1996) demonstrated selective activation of the anterior hypothalamus bymodafinil, and the authors of that study also demonstrated thatadministration of modafinil to cats at a wake-promoting dose failed tocause activation of the TMN of the posterior hypothalamus. A similarstudy of wake-promoting doses of modafinil administered to rats (Engberet al., Neuroscience, 87:905-911 (1998)) also demonstrated thatmodafinil-induced wakefulness was not associated with activation of theTMN. Thus, while activation of the TMN has been implicated in normalwakefulness, the studies of these researchers has clearly taught thatTMN activation was not involved in modafinil-induced wakefulness.

[0031] The present invention arises in part from the discovery thatmodafinil, when administered at wakefulness-promoting doses, does resultin a stimulation of activity in the TMN of the posterior hypothalamus.Modafinil administration in rats reduced the activity of the neurons inthe ventrolateropreoptic area (VLPO) of the hypothalamus, which areknown to inhibit the activity of wake-promoting histaminergic neurons inthe TMN during sleep. Activation of this histaminergic pathway bymodafinil results in cortical activation and wakefulness. Thus, itappears that the physiologic basis for the wake-promoting actions ofmodafinil involves disinhibition of histaminergic neurons of the TMN byinhibitory actions on the VLPO. This represents the first pharmacologicagent known to produce wakefulness by activation of the TMN.

[0032] Furthernore, because the lateral hypothalamus is classicallyimplicated in eating behavior, activation of this area by modafinilindicates that administration of modafinil will also be useful incontrol of eating disorders or for appetite enhancement. Because thepresent inventors also discovered that this area is innervated by orexinneurons, they were led to the discovery that modafinil is able tostimulate orexin activity in the hypothalamus and is thus useful as anagent in the treatment of eating disorders.

[0033] The present invention arose from studies in whichdouble-immunostaining techniques were used determine that orexin neuronsprojected directly onto the central nervous system nuclei known to beimportant in sleep-wakefulness regulation. The distribution oforexin-immunoreactive terminals was similar to that previously reported,including particularly dense innervation of the locus coeruleus, dorsaland median raphe nuclei, and tuberomammillary nucleus (Peyron et al.,Neurosci. 18:9996-10015, 1998; Elias et al., J. Comp. Neurol.402:442-459, 1998; Date et al., Proc. Natl. Acad. Sci. USA, 96:748-753,1999). Innervation was also observed in the pedunculopontine nucleus,the lateral dorsal tegmental nucleus, the horizontal and vertical limbsof the diagonal band of Broca, and the medial septal nucleus, aspreviously reported (Peyron et al., Neurosci. 18:9996-10015, 1998; Nambuet al., Brain Res. 827:243-260, 1999). Double-label immunohistochemistrywas performed in these sites in both rat and mouse brains. listaminergicneurons in the tuberomammillary nucleus (adenosinedeaminase-immunoreactive) received very dense orexin innervation on cellbodies and on proximal dendrites. Noradrenergic neurons in the locuscoeruleus received a similar dense innervation by orexin immunoreactivefibers. Somatic and dendritic appositions on tyrosinehydroxylase-immunoreactive cells were best observed on solitary neuronson the edges of the locus coeruleus. Serotonergic neurons in the dorsaland median raphe nucleus also were densely innervated. It was alsoobserved that serotonergic neurons in the dorsal raphe are specificallytargeted by orexin terminals. In the mouse brain, cholinergic neurons inthe pedunculopontine nuclei, lateral dorsal tegmental nucleus, diagonalband, and medial septal nuclei, received orexin innervation. Theinnervation of cholinergic cells was particularly dense in the ratbrain. In all sites, apparent somatic and dendritic appositions wereobserved in the chemically characterized neurons.

[0034] To determine that modafinil might act through orexin neurons,wild-type mice were injected at noon with modafinil (150 mg/kg i.p.), orvehicle, and sacrificed 2 hours later. Brains were removed, doubleimmunostained for orexin and Fos (an indicator of neuronal activity),and cells were counted in the perifornical region. The number oforexin-immunoreactive neurons was the same in both groups (44-47cells/section), but the modafinil-treated group had over three times asmany Fos-immuno-reactive neuronal nuclei (38 in the modafinil-treatedmice vs. 11 in the vehicle controls; p=0.01). Within the population oforexin-immunoreactive neurons, modafinil induced a 9-fold increase inthe number of Fos-immunoreactive cells (64% double labeled neurons inthe modafinil group vs. 7% in the vehicle group, p=0.01) (FIG. 1). Thus,in the lateral hypothalamus, modafinil treatment is associated withactivation of orexin neurons, and is thus useful as a treatment foreating disorders or for increasing appetite.

[0035] Modafinil also strongly activates orexin neurons in the lateralhypothalamus. However, it is difficult to conclude that modafinilpromotes wakefulness solely through orexin neurons because it alsoinduces neuronal activation in other brain regions implicated insleep-wakefulness regulation, such as the suprachiasmatic nucleus,anterior hypothalamic area (Lin et al., Proc. Natl. Acad. Sci. USA,93:14128-14133, 1996), tuberomammillary nucleus, and locus coeruleus .Since orexin neurons heavily innervate the tuberomammillary nucleus andlocus coeruleus (Peyron et al., Neurosci. 18:9996-10015, 1998), it ispossible that modafinil may activate the orexin system which thenrecruits other arousal regions.

[0036] Prior to any invention disclosed or claimed herein, modafinil wasknown in the art in the form of a therapeutic package, marketed underthe name Provigil®. Provigil® is a pharmaceutical product manufacturedby Cephalon, Inc. of West Chester, Pa. and is also marketed by Cephalon,Inc. Provigil® is supplied as tablets containing 100 mg or 200 mgmodafinil. In commercial use, modafinil-containing therapeutic packagesin the prior art were labeled and otherwise indicated for use innarcolepsy patients.

[0037] Accordingly, known in the prior art were therapeutic packagesproviding one or more unit doses of modafinil as an active ingredientthereof, supplied in a finished pharmaceutical container that containsaid unit doses, and further contained or comprised labeling directingthe use of said package in the treatment of a human disease or conditionas described above. n the provided literature accompanying apharmaceutical container are instructions that the daily dosage ofmodafinil is 200 mg/day given as a single dose in the morning. Although400 mg/day was well tolerated in clinical trials, 200 mg/day is theoptimum wakefulness promoting dose in adult humans.

[0038] All of the compositions and methods disclosed and claimed hereincan be made and executed without undue experimentation in light of thepresent disclosure. While the compositions and methods of this inventionhave been described in terms of preferred embodiments, it will beapparent to those of skill in the art that variations may be applied tothe compositions and/or methods and in the steps or in the sequence ofsteps of the methods described herein without departing from theconcept, spirit and scope of the invention. More specifically, it willbe apparent that certain agents which are both chemically andphysiologically related may be substituted for the agents describedherein while the same or similar results would be achieved. All suchsimilar substitutes and modifications apparent to those skilled in theart are deemed to be within the spirit, scope and concept of theinvention as defined by the appended claims.

What is claimed is:
 1. A method of treating an eating disorder in amammal comprising administering to said mammal an amount of a modafinilcompound effective to stimulate the appetite of said mammal.
 2. A methodof promoting weight gain in a mammal comprising administering to saidmammal an amount of a modafinil compound effective to stimulate theappetite of said mammal.
 3. A method of increasing appetite in a mammalcomprising administering to said mammal an amount of a modafinilcompound effective to increase the appetite of said mammal.
 4. A methodof treating a mammal suffering from the symptoms of an eating disordercomprising administering to said mammal a pharmaceutical compositioncomprising a modafinil compound in an amount effective to stimulateorexin activity in the central nervous system of said mammal.
 5. Themethod of any of claims 1-4, wherein said modafinil compound ismodafinil.
 6. The method of any of claims 1-4, wherein said mammal is ahuman.
 7. The method of claim 2 or 3, wherein said mammal is adomesticated animal useful for producing meat.
 8. The method of claim 7,wherein said mammal is a bovine, ovine, caprine, or porcine animal. 9.The method of any of claims 1-4, wherein said mammal is human sufferingfrom, or susceptible to an eating disorder or to wasting associated witha disease.
 10. The method of claim 9, wherein said eating disorder isanorexia nervosa.
 11. The method of any of claims 1-4, wherein saideffective amount is from about 1 to about 400 mg per daily dose.
 12. Themethod of any of claims 1-4, wherein said effective amount is from about100 to about 400 mg per daily dose.
 13. The method of any of claims 1-4,wherein said effective amount is about 200 mg per daily dose.
 14. Themethod of any of claims 1-4, wherein said effective amount is an amountthat is effective to achieve a serum level of modafinil of from about0.05 to about 20 g/ml in said mammal.
 15. The method of any of claims1-4, wherein said effective amount is an amount that is effective toachieve a serum level of modafinil of from about 1 to about 20 :g/ml insaid mammal.
 16. The method of any of claims 1-4, wherein said modafinilcompound is formulated for oral administration.
 17. The method of any ofclaims 1-4, wherein said modafinil compound is formulated as a tablet.18. The method of claim 17, wherein said tablet contains lactose, cornstarch, magnesium silicate, croscarmellose sodium, povidone, magnesiumstearate, or talc in any combination.
 19. The method of any of claims1-4, wherein said modafinil compound is incorporated into a food productor a liquid.
 20. A pharmaceutical composition in unit dose form, for usein treating an eating disorder in a subject susceptible to thedevelopment of or suffering from an eating disorder, which comprises: anamount of a modafinil compound such that one or more unit doses thereofare effective to stabilize or improve the symptoms of an eating disorderin said subject upon periodic administration.
 21. A veterinarycomposition in unit dose form, for use in increasing appetite in ananimal, which comprises: an amount of a modafinil compound such that oneor more unit doses thereof are effective to increase the appetite of ananimal upon periodic administration.
 22. The composition of claim 21wherein said animal is a weanling.
 23. The composition of claim 20 or21, wherein said modafinil compound is modafinil.
 24. The composition ofclaim 20, wherein said subject or said mammal is a human.
 25. Thecomposition of claim 21, wherein said mammal is a domesticated animaluseful for producing meat.
 26. The composition of claim 25, wherein saidmammal is a bovine, ovine, caprine, or porcine animal.
 27. Thecomposition of claim 20, wherein said subject or said mammal is a humansuffering from, or susceptible to an eating disorder or to wastingassociated with a disease.
 28. The composition of claim 27, wherein saideating disorder is anorexia nervosa.
 29. The composition of claim 20,wherein said effective amount is from about 1 to about 400 mg per dailydose.
 30. The composition of claim 20, wherein said effective amount isfrom about 100 to about 400 mg per daily dose.
 31. The composition ofclaim 20, wherein said effective amount is about 200 mg per daily dose.32. The composition of claim 20, wherein said effective amount is anamount that is effective to achieve a serum level of modafinil of fromabout 0.05 to about 20 :g/ml in said subject.
 33. The composition ofclaim 20, wherein said effective amount is an amount that is effectiveto achieve a serum level of modafinil of from about 1 to about 20 :g/mlin said subject.
 34. The composition of claim 20 or 21, wherein saidcomposition comprising a modafinil compound is formulated for oraladministration.
 35. The composition of claim 20 or 21, wherein saidcomposition comprising a modafinil compound is formulated as a tablet.36. The composition of claim 35, wherein said tablet contains lactose,corn starch, magnesium silicate, croscarmellose sodium, povidone,magnesium stearate, or talc in any combination.
 37. The composition ofclaim 20 or 21, wherein said modafinil compound is incorporated into afood product or a liquid.
 38. A therapeutic package for dispensing to,or for use in dispensing to, a mammal being treated for an eatingdisorder, comprising: (1) one or more unit doses, each such unit dosecontaining an amount of a modafinil compound such that said one or moreunit doses thereof are effective to stabilize or improve a symptom of aneating disorder in said mammal upon periodic administration and the unitdoses being administered periodically; and (2) a finished pharmaceuticalcontainer therefor, said container containing said unit dose or unitdoses and labeling directing the use of said package in the treatment ofsaid mammal.
 39. The therapeutic package according to claim 38, whereinthe unit dose is adapted for oral administration.
 40. The therapeuticpackage according to claim 38, wherein the amount of the modafinilcompound contained in each unit dose provides a dose effective toachieve a serum level of modafinil in said mammal of from about 0.05 toabout 20 :g/ml.
 41. The therapeutic package according to claim 38,wherein the amount of the modafinil compound contained in each unit doseprovides a dose effective to achieve a serum level of modafinil in saidmammal of from about 1 to about 20 :g/ml.
 42. The therapeutic packageaccording to claim 38, wherein the amount of the modafinil compoundcontained in each unit dose provides a dose effective to achieve a serumlevel of modafinil in said mammal of from about 1 to about 10 :g/ml. 43.The therapeutic package according to claim 38, wherein the amount of themodafinil compound contained in each unit dose provides a dose effectiveto achieve a serum level of modafinil in said mammal of from about 0.5to about 1.5 :g/ml.
 44. The therapeutic package according to claim 38,wherein the unit dose comprises a tablet for oral administration. 45.The therapeutic package according to claim 38, wherein said modafinilcompound is modafinil.
 46. The therapeutic package according to claim38, wherein said mammal has or is susceptible to anorexia nervosa. 47.The therapeutic package according to claim 44, wherein said tabletcomprises lactose, corn starch, magnesium silicate, croscarmellosesodium, povidone, magnesium stearate, or talc.
 48. The therapeuticpackage according to claim 38, wherein said mammal is a human.